ORCID

0000-0002-9466-0928

Date of Award

2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Nursing

First Advisor

Dimitry N. Krementsov

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system(CNS) in which the myelin sheaths of neurons are attacked. The resulting demyelination, as well as incidental immune-mediated neurodegeneration, contributes to variable disability that increases over time. Environmental risk factors play a major role in both disease initiation and progression, and the gut microbiome is of growing interest as a modifiable risk factor in MS. Research on the gut microbiome and MS has uncovered patterns associated with MS disease status and progression, with Akkermansia muciniphila arguably the most notable bacterium studied for these purposes. Literature comparing people with MS to healthy controls has consistently found A. muciniphila associated with MS, however, studies comparing the abundance of A. muciniphila and MS disease severity have often linked A. muciniphila with reduced disability, leading to a lack of consensus on the role that A. muciniphila plays in the disease. To address this lack of consensus, we utilized an animal model of MS, experimental autoimmune encephalomyelitis (EAE), that mimics the disease process of MS in mice and assessed disease severity in combination with experimental approaches involving A. muciniphila. Initially, treatment of SPF A. muciniphila-colonized mice with A. muciniphila, akin to probiotic supplementation in humans, failed to produce any significant differences in EAE severity or increase A. muciniphila levels. Thus, we pivoted to leveraging two complex and divergent A. muciniphila-free microbiomes in mice that we colonized with A. muciniphila or maintained as A. muciniphila-free to isolate the impact of A. muciniphila colonization on ecologically distinct microbiome and subsequent severity of CNS autoimmunity. We observed exacerbated disease severity and an amplified Th17 CNS immune response in A. muciniphila-colonized mice in a microbiome context-dependent manner. To better understand the underlying differences in the gut and how A. muciniphila colonization alters the microbiome as a whole, we analyzed full-length 16S DNA sequences. We observed a reduction in Clostridia in the microbiome model in which A. muciniphila colonization worsened diseases, whereas the A. muciniphila-free counterpart microbiome was relatively rich in Clostridia. Broadly, commensal Clostridia metabolize dietary fiber and produce short-chain fatty acids, small molecule metabolites that have been shown to drive tolerogenic immune responses over inflammatory responses. Furthermore, profiling predicted functional pathways, analyzing specific SCFAproducing bacteria, and quantifying SCFA by mass spectrometry showed reduced SCFAs and SCFA production. Additionally, supplementation with dietary fiber prior to EAE severity in the Clostridia-rich microbiome model ameliorated disease. Conversely, we wondered if A. muciniphila was contributing to a local inflammatory state in the gut, but found no such evidence from analyzing lipocalin-2, a measure of intestinal inflammation. Interestingly, however, we found increased IgA responses after EAE induction and in A. muciniphila-colonized mice that did not exhibit increased disease severity, suggesting that host response to A. muciniphila may contribute to the abundance and consequences of A. muciniphila colonization. Together, our results demonstrate 1) a concordance of A. muciniphilacolonization that pairs with a reduction in Clostridia and SCFAs that may antagonize CNS autoimmunity, and 2) the importance of the microbiome context in understanding how microbes contribute to health and disease.

Language

en

Number of Pages

265 p.

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